Taxane Analogues Research Articles

Abstract 1074: Cellular uptake and metabolism of MT1-MMP-activated taxane prodrugs

Abstract ICT3205 is a targeted cytotoxic agent, comprised of an MT1-MMP-specific peptide and a paclitaxel warhead. Paclitaxel, originally approved in 1992, is one of the most commonly used chemotherapies for various cancer types, but is often characterized by its dose-limiting toxicity and low aqueous solubility. Tumor-targeted prodrugs are a promising strategy for the selective delivery of taxanes to prostate tumors, especially given the results of STAMPEDE trial1. Previous work has shown that ICT3205 is selectively metabolized in tumor tissue over the normal tissue, and that this is specifically mediated by MT1-MMP2. In vivo studies have demonstrated that when administered at an equimolar dose to paclitaxel, ICT3205 has a superior anticancer effect, with an absence of systemic toxicity. In this study we aim to further investigate the cellular uptake and metabolism of ICT3205 and other taxane analogues in MT1-MMP +ve (HT1080) and MT1-MMP -ve (MCF-7) cells in vitro. The compound will be also studied in the PC3 prostate cancer cell line, since it has been demonstrated before that there is a good correlation between MT1-MMP protein and mRNA expression. ICT3205 and analogues have been synthesized, and purified by semi-preparative HPLC. We report the tumor-specific metabolism of ICT3205 in prostate tumors ex vivo, and we are currently studying its cellular uptake and metabolism in MT1-MMP +ve and MT1-MMP -ve cancer cell-lines using HPLC, mass spectrometry and immunofluorescent microscopy. Moreover, ex vivo metabolism studies are performed on the analogues, while they will be also assessed for their metabolism and cellular uptake. These data will provide a better understanding of the mechanism of uptake and metabolism of this type of peptide prodrugs, and will provide the basis for the future synthesis and optimization of these prodrugs. 1.James ND et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomized controlled trial. Lancet. 2016;387(10024):1163-772.Loadman PM et al. Improved delivery of paclitaxel to prostate tumors: a membrane-type matrix metalloproteinase (MT-MMP)-targeted approach. Cancer Res. 2016;76:3 Citation Format: Athina Polykandritou, Alexandra Serre, Hannah Spencer, Goreti R. Morais, Amanda Race, Steven Shnyder, Paul Loadman, Robert A. Falconer. Cellular uptake and metabolism of MT1-MMP-activated taxane prodrugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1074.

Abstract 1753: Deregulation and therapeutic potential of targeting IRAK3 as chronic inflammation suppressor in prostate cancer

Abstract Chronic inflammation is emerging as a targetable driver of tumorigenesis. During chronic inflammation, several inflammatory molecules are either activated or suppressed for a prolonged time. The oncogenic role of many of these inflammatory genes in prostate cancer (PCa) remains unexplored despite the increasing association of chronic inflammation with PCa initiation, progression, and therapy resistance in the scientific literature. The overarching goal of this study was to identify deregulated inflammatory suppressor genes, including interleukin-1 receptor-associated kinases 3 (IRAK3) as biomarkers for inflammation-driven PCa aggressiveness or progression. To achieve this, we utilize cutting-edge integrative (epi)genomic and transcriptomic techniques to investigate the role of IRAK3 in PCa progression, as well as the therapeutic potential of targeting IRAK3 in PCa. An array of computational tools was deployed to analyze Illumina HumanMethylation450K and whole exome RNAseq clinical datasets acquired from TCGA and cBioportal databases to identify differentially methylated and altered or expressed inflammatory suppressor genes in PCa patients/samples. We identified six inflammatory suppressor genes (IRAK3, TOLLIP, SOCS1, RNF216, IL1RL1, and TNFAIP3) to be significantly deregulated in indolent (n=493), metastatic (n=212), and lethal (n=50) PCa patients/samples. The expression patterns of these genes were correlated with clinical traits, such as age, progression-free status, overall survival status, biochemical recurrence, pathology as well as metastatic status using weighted gene co-expression network analysis, which identified IRAK3 as one of the top genes to explore. MutSigCV and GISTIC tools were used to identify somatic mutations and copy-number alterations. IRAK3 was found to be downregulated in most indolent, metastatic and lethal PCa samples. Its low expression correlated significantly with the progression, metastatic and recurrence statuses of the PCa. The genome-wide DNA methylation analysis of the 16 CpG probes identified in IRAK3 reveals hypermethylation (b-value or m-value < 0.01) at the promoter regions, which may be responsible for the observed transcriptional repression of IRAK3. Further analysis shows that DNA methylation is higher in PCa samples with mutated IRAK3 compared to those without the mutation. Mechanistic studies using genome-wide CRISPR-Cas9 gene-editing techniques were performed to create IRAK3+/+ or IRAK3-/- PCa clones. Using a series of bioassays, IRAK3 reactivation was found to inhibit PCa cell proliferation, migration, colony formation, and chemoresistance as well as induce apoptotic cell death. IRAK3+/+ PCa cells responded well to Taxane analogs compared to IRAK3-/- PCa cells. In conclusion, we have been able to demonstrate the tumor suppressor potential of IRAK3 in prostate cancer cells. Citation Format: Saheed Oluwasina Oseni, Corey Naar, Magdalah Philemy, Genesis Acosta Laguer, Faika Ambrin, Sharlanda Metayer, Ariana Perez, Javoncia Betty, Preethika Praveen, James Hartmann, Mirjana Pavlovic, James Kumi-Diaka. Deregulation and therapeutic potential of targeting IRAK3 as chronic inflammation suppressor in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1753.

Synthesis and biological activity of C-7, C-9 and C-10 modified taxane analogues from 1-deoxybaccatin VI

A series of C-7, C-9 and C-10 modified taxane analogues were synthesized and their in vitro anticancer activities against three human cancer cell lines: A-549 (human lung cancer cell line), MDA-MB-231 (human breast cancer cell line), A-549/T (human lung cancer resistant cell line) were studied. The novel 1-deoxybaccatin VI derivatives modified with carbonate group at C-9 and C-10 positions enable the behavior of these compounds to be evidently distinct from other similar compounds. The strong cytotoxicity in the three cell lines, especially in drug-resistant cell line, showed by the newly synthesized taxane analogues indicated them as potential lead compounds for anticancer drug design.

Design, synthesis of novel C-3′-N-sulfonyl modified taxane analogues from 1-deoxybaccatin VI and their impact on anti-HCC activity

A new series of C-3′-N-sulfonyl paclitaxel analogs were designed and synthesized from 1-deoxybaccatin VI and their structures were confirmed by 1H NMR, 13C NMR and high resolution MS. The synthesized compounds were evaluated for their in vitro anti-Hepatocellular carcinoma (HCC) activity against human hepatoma (HepG2) cell line. Bioassay results showed that compounds 17c, 17d and 17f exhibited more potent inhibitory activity against HepG2 cell line in comparison with paclitaxel. It is suggested that paclitaxel analogs containing the C-3′-N-sulfonyl could be considered as a precursor structure for further synthesis of more potent analogues.

Synthesis and biological evaluation of C-13, C-14 modified taxane analogues from 1-deoxybaccatin VI

Four C-13, C-14 side chain modified 9(R)-hydroxy-1-deoxy-taxane analogues 15, 16, 19 and 22 were semi-synthesized from 1-deoxybaccatin VI. The in vitro antitumor activity of these compounds was evaluated against A549 and A2780 cell lines. The preliminary SAR analysis showed that introduction of oxygen-containing group on C-14 could improve the cytotoxic activities.

Lx2-32c inhibits the formation of mammosphere from MDA-MB-231 cells and induces apoptosis involving in down-regulating FoxM1

Cancer stem cells (CSCs) are a subset of cancer cells which have self-renewal ability and exist in various tumors. Inhibition of CSCs self-renewal is considered as a new method for tumor therapy. A novel semi-synthetic taxane analogue, Lx2-32c, could overcome drug resistance in various cancer cell lines. In this study, it was found that Lx2-32c inhibited the proliferation and mammosphere formation of MDA-MB-231-derived cancer stem cell-like cells (MCSCLCs) and induced apoptosis, as well as down-regulated the expression of FoxM1 and CD44 in MCSCLCs. Simultaneously, it was proved that Lx2-32c combined with thiostreption, a FoxM1 inhibitor inhibited proliferation and mammosphere formation of MCSCLCs and induced apoptosis to a more extent than Lx2-32c alone; thiostreption could also enhance the effect of Lx2-32c of reduction of the expression of FoxM1 and CD44. All of these results indicated that Lx2-32c is a novel semi-synthetic taxane analogue which inhibits the self-renewal of MCSCLCs cells and induces apoptosis involving in down-regulating FoxM1.

Characterization of metabolites of larotaxel in rat by liquid chromatography coupled with Q exactive high-resolution benchtop quadrupole orbitrap mass spectrometer

1. Liquid-chromatography (LC) high-resolution (HR) mass spectrometry (MS) analysis can record HR full scans for drug metabolism studies. Larotaxel is a taxane analog that has the potential for the treatment of various types of cancer.2. In this study, the metabolism of larotaxel was evaluated after an intravenous dose of 8 mg/kg via the caudal vein to healthy rats and its metabolites were characterized by high performance liquid chromatography coupled with a Q Exactive high-resolution benchtop quadrupole orbitrap mass spectrometer. Rat bio-samples were separated on a Capcell Pak C18 column (2.1 i.d. × 100 mm; 2.7 μm) with mobile phase of acetonitrile and water.3. As a result, a total of 34 metabolites were detected and identified by comparing the molecular masses, retention times and spectral patterns of the analytes with those of the parent drug. Three metabolites were confirmed by comparison with reference substances.4. The prominent metabolites were mainly hydroxyl, dihydroxyl, trihydroxyl and 10-desacetyl analogs of larotaxel, some of which resulted from oxidation of the tert-butyl groups on the side chain and further oxidation and cyclization of the tert-butyl hydroxylated metabolites.

Overview of the Formulations and Analogs in the Taxanes' Story.

Taxanes are a family of diterpenes produced by the yews (Taxus genus) that are extensively used in chemotherapy. The family encompasses paclitaxel, docetaxel and the recently added cabazitaxel, all of which were proven to be promising anti-cancer drugs. Due to the over harvesting danger threatening the yew trees as well as the many challenges faced by taxane-based chemotherapy, new formulations, analogs and delivery systems are required. Here, we undertook a structured search of the bibliographical database PubMed for peerreviewed research papers relying on key words and date of publication and organized the information based on the method of taxane drug delivery. Papers retrieved were from journals with significant impact and comparable scope. A total of 126 papers were reviewed, 81 of which published work related to the taxane formulations and nanoparticles, and 22 focused on the analogs derived from the three taxanes. Although recent articles investigate the effectiveness of taxane formulations, most of these formulations are still at the pre-clinical level. However, many of the taxane analogs are currently in clinical trials as second line treatment of aggressive cancers or are used in combination with other chemotherapeutic drugs. The findings corroborate the importance of developing new drug delivery strategies and taxane analogs to improve the efficacy of currently used chemotherapeutic drugs. This finding is further supported by the FDA-approved formulation of paclitaxel that eliminates the need for toxic solvents for drug administration, and the docetaxel analog cabazitaxel which has decreased affinity for efflux pumps.

Towards taxane analogues synthesis by dienyne ring closing metathesis

The synthesis of highly functionalized 16,17,18-trinortaxane analogues based on a dienyne cyclization is described.

Syntheses and biological evaluation of C-3′-N-acyl modified taxane analogues from 1-deoxybaccatin-VI

A series of side-chain modified taxane analogues were synthesized and their in vitro anticancer activities against four human cancer cell lines: MDA-MB-231 (human breast cancer), PC-3 (human prostatic cancer), HepG2 and H460 (human hepatoma) were studied. The three hydroxyl groups at C-7, C-9 and C-10 enable the behavior of these compounds to be evidently distinct from other similar compounds. The strong cytotoxicity in the four cell lines showed by the newly synthesized taxane analogues 13a and 13d indicated them as potential lead compounds for anticancer drug design.

"Effect of the drug transporters ABCB1, ABCC2, and ABCG2 on the disposition and brain accumulation of the taxane analog BMS-275,183".

BMS-275,183 is a novel oral C-4 methyl carbonate analogue of paclitaxel. Recently, a drug-drug interaction between BMS-275,183 and benzimidazole proton pump inhibitors (PPIs) was suggested in clinical trials resulting in elevated drug exposure and toxicity. We explored whether the interaction takes place at the level of P-glycoprotein (Pgp, MDR1, ABCB1), Breast Cancer Resistance Protein (BCRP, ABCG2) and MRP2 (ABCC2) using in vitro and in vivo models. In vitro cell survival, drug accumulation, efflux and transport studies with BMS-275,183 were performed employing MDCKII (wild-type, MDR1, BCRP, MRP2) and LLCPK (wild-type and MDR1) cells. In vivo the pharmacokinetics and tissue distribution of BMS-275,183 after p.o. and i.v. administration were explored in Mdr1a/1b(-/-) and wild-type mice, in presence or absence of the PPI pantoprazole. Results In vitro, BMS-275,183 was found to be a good substrate for MDR1, a moderate substrate for MRP2 and not a substrate for BCRP. In vivo, oral bioavailability, plasma AUC0-6h and brain concentrations were significantly 1.5-, 4-, and 2-fold increased, respectively, in Mdr1a/1b(-/-) compared with wild-type mice (p < 0.001). However, oral co-administration of pantoprazole (40 mg/kg) did not alter the pharmacokinetics of BMS-275,183 in wild-type mice. Conclusions BMS-275,183 is efficiently transported by Pgp and to a lesser extent by MRP2 in vitro. Genetic deletion of Pgp significantly altered the pharmacokinetics and brain distribution of p.o. and i.v. administered BMS-275,183 in Mdr1a/1b-/- compared to wild-type mice. Oral co-administration of BMS-275,183 with pantoprazole did not affect the pharmacokinetics of BMS-275,183 in wild-type mice, suggesting no interaction with PPI at the dose employed.

Abstract 1945: A novel self assembled taxane nanoparticles for breast cancer chemotherapy

Abstract Breast cancer is the most frequently diagnosed form of cancer and a second leading cause of cancer deaths among women in the United States, with an estimated 207,090 new cases and 39,840 deaths since the beginning of 2010. Taxane-based chemotherapeutic agents are extensively used as a treatment for breast cancer and have shown important clinical benefits in both adjuvant and metastatic settings. However, the therapeutic efficacy of these drugs is hampered by limitations such as poor water solubility, narrow therapeutic indices and significant off-target toxicities which limit its dose escalations and treatment frequency. Also, current drug delivery strategies often suffer from constraints such as lower potency, low loading, non-biocompatibility/ non-biodegradability and uncontrolled release of the drug. Clearly, there is an urgent need for a paradigm shift in the strategies for the development of drug delivery vehicles for breast cancer management. We propose a novel approach in the design of nanomedicine where an active molecule can self-assemble into a nanoparticle resulting in increased loading, improved antitumor outcome and reduced off-target side effects. Different taxane analogs were attached to cholesterol using an acid labile linker. The self assembly of taxane-cholesterol conjugate was facilitated by phosphatidylcholine and DSPE-PEG to form well defined nano-sized particles. The loading of 10-15 μg/μL of drugs was obtained and sustained release of drugs was observed at pH 5.5 over 48h. In a preliminary cell viability studies, the taxane nanoparticles showed comparable efficacy to drug alone. Next, in order to achieve tumor specific homing of the nanoparticles, we plan to incorporate multiple copies of iRGD peptide on the nanoparticle surface that will bind to αvβ3 integrins overexpressed on the endothelium of tumor vessels and help in effective internalization of nanoparticles. The optimum density of peptides on the nanoparticle surface will be achieved by conjugating the peptide to DSPE-PEG. We believe that this study will not only uncover a novel and most effective nanotechnology-based approach for breast cancer treatment but will also eventually lead to an improvement in the quality of life of patients at minimum cost. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1945. doi:1538-7445.AM2012-1945

Novel Hydrophilic Taxane Analogues inhibit Growth of Cancer Cells

In our era there has been several anti-cancer drugs which have undergone both experimental and clinical trials; however, due to their poor solubilities, numerous side effects, insufficient bioavailability and poor compliance, many have resulted into poor outcomes. Therefore, our aim was to investigate the effects of novel hydrophilic taxanes analogues CQMU-0517 and CQMU-0519 on growth of A549 lung, SKVO3 ovary and MCF7 breast carcinoma cell lines. Different concentrations of original paclitaxel, CQMU-0517, original docetaxel and CQMU-0519 were utilized on three cell lines, where cell growth was assessed using cell culture kit-8 and flow cytometry analysis. The results unveiled that CQMU-0517 and CQMU-0519 suppressed cell growth in the three particular cell lines, cell cycle arrest being evident in the G2/M phase. Hence, the results showed that these new taxane analogues have potential and warrant future clinical trials.

Scalable enantioselective total synthesis of taxanes

Taxanes are a large family of terpenes comprising over 350 members, the most famous of which is Taxol (paclitaxel) — a billion-dollar anticancer drug. Here, we describe the first practical and scalable synthetic entry to these natural products via a concise preparation of (+)-taxa-4(5),11(12)-dien-2-one, which possesses a suitable functional handle to access more oxidised members of its family. This route enabled a gram-scale preparation of the ”parent” taxane, taxadiene, representing the largest quantity of this naturally occurring terpene ever isolated or prepared in pure form. The taxane family’s characteristic 6-8-6 tricyclic system containing a bridgehead alkene is forged via a vicinal difunctionalisation/Diels–Alder strategy. Asymmetry is introduced by means of an enantioselective conjugate addition that forms an all-carbon quaternary centre, from which all other stereocentres are fixed via substrate control. This study lays a critical foundation for a planned access to minimally oxidised taxane analogs and a scalable laboratory preparation of Taxol itself.

Gram-scale preparation of paclitaxel precursors for synthesis of taxane analogs

Gram-scale preparation of paclitaxel precursors for synthesis of taxane analogs

Management strategies for recurrent platinum-resistant ovarian cancer.

Although ovarian cancer is often a chemosensitive malignancy, patients who are resistant to platinum-based chemotherapy represent a therapeutic challenge. Currently, the only drugs that are US FDA approved to treat this subset of patients are paclitaxel, pegylated liposomal doxorubicin (PLD) and topotecan. The response rates with these agents is in the 10-15% range and overall survival is around 12 months. Other drugs that have shown some activity in platinum-resistant ovarian cancer include the taxane analogues, oral etoposide, pemetrexed and bevacizumab. Unfortunately, randomized phase III trials of second-line chemotherapy in patients with platinum-resistant ovarian cancer have not shown an advantage over existing therapy with respect to progression-free survival or overall survival. The only trial that has reported a significant progression-free survival advantage over standard therapy is a randomized phase II trial of PLD with or without EC145, a folate-linked vinca alkaloid. Final survival results of this trial are pending.

QSAR modeling of taxane analogues against colon cancer

Although taxanes such as paclitaxel and docetaxel are the two most important clinically available anticancer drugs for the treatment of various cancers (including colon cancer), the success of these two drugs has been tempered by the development of various unbearable side effects as well as multi-drug resistance. Therefore, it is essential to search new taxane analogues with improved anticancer activity and fewer side effects to gain the maximum benefits for colon cancer patients. In this paper, four series of taxane derivatives were used to correlate their inhibitory activities against colon cancers mainly with the hydrophobic and steric descriptors of their substituents in order to gain a better understanding of their chemical–biological interactions. QSAR results from this paper have suggested that the steric and hydrophobic parameters of the substituents are the two most important determinants for the activities of taxane analogues (under consideration) against colon cancers, with a major contribution coming from the molar refractivity of the substituents. Statistical diagnostics, internal validation, and external validation tests have validated all the QSAR models.

Larotaxel: broadening the road with new taxanes

Significant advances in cancer treatment have been achieved with novel targeted and state-of-the-art treatments. While the targeted treatments have received much attention in recent years, the more ‘traditional’ chemotherapeutic agents continue to play an important role in several malignancies. Former taxanes such as docetaxel and paclitaxel, with their broad anticancer activity, have contributed significantly to the improved treatment of a number of neoplastic diseases. Unfortunately, until now, the achievements obtained with these compounds have been mitigated by clinical limitations such as acquired or intrinsic resistance of tumors, poor CNS activity, allergic reactions and unfavorable toxicity profiles. Larotaxel (RPR 109881A) is a taxane analogue with a broad spectrum of activity and different toxicity profile and with the possible advantages of surpassing some mechanisms of resistance and penetrating into the CNS. The development path of this drug, its core clinical data and future treatment perspectives are discussed in this article.

Taxane Analogues against Lung Cancer: A Quantitative Structure–Activity Relationship Study

Lung cancer is the second most common cancer in both men (after prostate cancer) and women (after breast cancer). The microtubule-stabilizing taxane such as docetaxel is the only agent currently approved for both first- and second-line treatment of advanced non-small cell lung cancer. Although docetaxel has made significant progress in the treatment of lung cancers either using alone or in combination with various novel targeted agents, its use often results in various undesired side-effects. These limitations have led to the search for new taxane derivatives with fewer side-effects, superior pharmacological properties, and improved anticancer activity to maximize the induced benefits for lung cancer patients. Herein, four series of taxane derivatives were used to correlate their inhibitory activities against lung cancer cells with hydrophobic and steric descriptors to gain a better understanding of their chemical-biological interactions. A parabolic correlation with MR(Y) is the most encouraging example, in which the optimum value of this parameter is well defined. On the basis of this quantitative structure-activity relationship model, six compounds (3-23 to 3-28) are suggested as potential synthetic targets. Internal (cross-validation (q(2)), quality factor (Q), Fischer statistics (F ) and Y-randomization) and external validation tests have validated all the quantitative structure-activity relationship models.

Metabolism and Excretion of an Oral Taxane Analog, [14C]3′-tert-Butyl-3′-N-tert-butyloxycarbonyl-4-deacetyl-3′-dephenyl-3′-N-debenzoyl-4-O-methoxy-paclitaxel (BMS-275183), in Rats and Dogs

3'-tert-Butyl-3'-N-tert-butyloxycarbonyl-4-deacetyl-3'-dephenyl-3'-N-debenzoyl-4-O-methoxy-paclitaxel (BMS-275183) is a taxane analog that has the potential for oral use in the treatment of various types of cancer. In this study, the metabolism and excretion of [(14)C]BMS-275183 were evaluated after a single oral administration of [(14)C]BMS-275183 to rats and dogs (15 and 1 mg/kg, respectively). To aid metabolite identification by mass spectrometry (MS), a stable labeled (phenyl-(13)C(6)) BMS-275183 was included in 1:1 ratio of (13)C(6)/(12)C in the dose administration. Fecal excretion was the major route of elimination for [(14)C]BMS-275183 in both species (85-86 and <9% of the dose in feces and urine, respectively). The highest radioactivity in plasma was observed at 1 h postdose, suggesting rapid absorption of the drug in both species. The total radioactivity in plasma was measurable up to 24 h postdose. Metabolites were identified by liquid chromatography-MS and/or NMR spectroscopy. [(14)C]BMS-275183 was the prominent component in rat and dog plasma and was detected up to 24 h along with various oxidative and hydrolytic metabolites. [(14)C]BMS-275183 was extensively metabolized in both species, forming mainly oxidative metabolites, and unchanged parent drug accounted for <3.5% of the administered dose in urine and feces. The prominent metabolites resulted from oxidation of the tert-butyl groups on the side chain and further oxidation and cyclization of the tert-butylhydroxylated metabolites. A total of 30 oxidative metabolites including M13, a prominent ester cleavage metabolite, were identified in rat and dog samples.